Interpretive Summary: Flunixin is a non-steroidal anti-inflammatory drug that is approved for use in cattle under restricted conditions. Cattle producers can ensure that flunixin residues do not contaminate meat or milk products by observing the proper administration route and the proper pre-harvest withdrawal period established by the US-FDA. However, the pre-harvest withdrawal period was determined by treating healthy, mature cattle with flunixin and measuring its depletion over time. In practice, flunixin is given to sick animals of all ages and production classes and the rate of drug depletion may change with animal maturity and with the health of an animal. The purpose of this study was to build a mathematical model which would simulate the depletion of flunixin from body tissues of cattle under a variety of situations. The model incorporated a large amount of data describing flunixin disposition and incorporated these data with parameters that describe physiological and biochemical processes of cattle. It is anticipated that the model could be used to predict withholding times for milk and/or meat of cattle treated with flunixin under non-traditional circumstances.

Technical Abstract:
Violative residues of flunixin in tissues from bob veal calves and cull dairy cows has been attributed to noncompliance with the FDA-approved route of administration and withdrawal time, however, the effect of administration route and physiological differences among animals on tissue residue depletion has not been determined. Therefore the objective of this work was to develop a physiologically based pharmacokinetc (PBPK) model to predict plasma, liver, and milk concentrations of flunixin in cattle following intravenous, intramuscular, or subcutaneous flunixn administration. The PBPK model included blood-flow-limited flunixin distribution in all tissues except liver and kidney, in which flunixin was assumed to be actively transported into the parenchyma allowing sequestration. Clearance was included in liver, kidney, and mammary gland, and enterohepatic recirculation and hydrolysis of conjugated metabolites were incorporated in the liver compartment. Point estimates for values of model parameters were obtained from literature sources or by model optimization with pharmacokinetic data. Model simulations of plasma, liver and milk flunixin concentrations following i.v., i.m., or s.c. administration compared well with empirical data and were used to identify influential model parameters. Age and disease-dependent pharmacokinetic processes, such as clearance, prolonged liver depletion, but the route of administration did not affect the estimated days to reach the tolerance concentration (0.125 ppm) in liver of cattle. However, the model suggested that the 36-h milk withholding time would be insufficient if flunixin is administered extravascularly to lactating cows because of the influence of absorption on milk concentrations.